Method for treating atherosclerosis employing an aP2 inhibitor and combination

ABSTRACT

A method is provided for treating atherosclerosis and related diseases, employing an aP2 inhibitor or a combination of an aP2 inhibitor and another antiatherosclerotic agent, for example, an HMG CoA reductase inhibitor such as pravastatin.

FIELD OF THE INVENTION

[0001] The present invention relates to a method for treatingatherosclerosis and related diseases, employing an aP2 inhibitor aloneor in combination with another type antiatherosclerotic agent.

BACKGROUND OF THE INVENTION

[0002] Fatty acid binding proteins (FABPs) are small cytoplasmicproteins which bind to fatty acids such as oleic acids which areimportant metabolic fuels and cellular regulators. Dysregulation offatty acid metabolism in adipose tissue is a prominent feature ofinsulin resistance and the transition from obesity to non-insulindependent diabetes mellitus (NIDDM or Type II diabetes).

[0003] aP2, an abundant 14.6 KDa cytosolic protein in adipocytes, andone of a family of homologous intracellular fatty acid binding proteins(FABPs), is involved in the regulation of fatty acid trafficking inadipocytes and mediates fatty acid fluxes in adipose tissue. G. S.Hotamisligil et al, “Uncoupling of Obesity from Insulin ResistanceThrough a Targeted Mutation in aP2, the Adipocyte Fatty Acid BindingProtein”, Science, Vol. 274, Nov. 22, 1996, pp. 1377-1379, report thataP2-deficient mice placed on a high fat diet for several weeks developeddietary obesity, but, unlike control-mice on a similar diet, did notdevelop insulin resistance or diabetes. Hotamisligil et al conclude that“aP2 is central to the pathway that links obesity to insulin resistance”(Abstract, page 1377).

[0004] DIALOG ALERT DBDR928 dates Jan. 2, 1997, Pharmaprojects No. 5149(Knight-Ridder Information) discloses that a major drug company “isusing virtual screening techniques to identify potential newantidiabetic compounds.” It is reported that “the company is screeningusing aP2, a protein related to adipocyte fatty acid binding protein.”

DESCRIPTION OF THE INVENTION

[0005] In accordance with the present invention, a method is providedfor treating atherosclerosis wherein a therapeutically effective amountof a drug which inhibits aP2 (aP2 inhibitor) is administered to a humanpatient in need of treatment.

[0006] In addition, in accordance with the present invention, a methodis provided for treating atherosclerosis, wherein a therapeuticallyeffective amount of a combination of an aP2 inhibitor and another typeof antiatherosclerotic agent is administered to a human patient in needof treatment.

[0007] Furthermore, in accordance with the present invention, a novelantiatherosclerotic combination is provided which is formed of a drugwhich inhibits aP2 and an antiatherosclerotic agent which functions by amechanism other than by inhibiting aP2. The aP2 inhibitor will beemployed in a weight ratio to the antiatherosclerotic agent (dependingupon its mode of operation) within the range from about 0.01:1 to about100:1, preferably from about 0.5:1 to about 10:1.

[0008] It will be appreciated that the method of the invention fortreating atherosclerosis employing an aP2 inhibitor alone or incombination with an antiatherosclerotic agent encompasses treating,reducing risk of, inhibiting, preventing and/or reducing or causingregression of atherosclerosis.

[0009] The method of the invention also encompasses preventing,inhibiting or reducing risk of cardiovascular and cerebrovasculerdiseases resulting from atherosclerosis, such as cardiac and/or cerebralischemia, myocardial infarction, angina, peripheral vascular disease andstroke.

[0010] The aP2 inhibitors suitable for use in the method of theinvention are compounds which bind to the aP2 protein and inhibits itsfunction and/or its ability to bind free fatty acids. The compounds willpreferably contain less than 60 carbon atoms, more preferably less than45 carbon atoms, and will contain less than 20 heteroatoms, morepreferably less than 12 heteroatoms. They contain a hydrogen bonddonator or acceptor group, preferably acidic in nature, which includes,but is not limited to, CO₂H, tetrazole, SO₃H, PO₃H, P(R) (O)OH (where Ris lower alkyl or lower alkoxy), OH, NHSO₂R′ or CONHSO₂R′ (where R′ islower alkyl), and thiazolidindione, and interacts (directly or throughan intervening water molecule), either by ionic or hydrogen bondinginteractions, with one, two, or three of the three amino acid residues,designated as Arg 106, Arg 126 and Tyr 128 in human aP2, within the aP2protein.

[0011] The compounds suitable for use herein preferably contain anadditional substituent, preferably hydrophobic in nature, which includethe following groups: alkyl, cycloalkyl, aryl, heteroaryl,cycloheteroalkyl, benzo-fused aryl and heteroaryl, and their substitutedcounterparts. Especially preferred are aryl and substituted aryl groups.More especially preferred is phenyl and halo or methyl substitutedphenyl.

[0012] The hydrophobic substituent binds to (in) and/or interacts with adiscrete pocket within the aP2 protein defined roughly by the amino acidresidues Phe 16, Tyr 19, Met 20, Val 23, Val 25, Ala 33, Phe 57, Thr 74,Ala 75, Asp 76, Arg 78 in human aP2. The through space distance from thehydrogen bond donor/acceptor group and the additional substituent groupis within the distance of about 7 to about 15 Angstroms.

[0013] The above compounds may be employed in the form ofpharmaceutically acceptable salts thereof and prodrug esters thereof.

[0014] The term “antiatherosclerotic agent” as employed herein refers toantihyperlipidemic agents including HMG CoA reductase inhibitors,microsomal triglyceride transfer protein (MTP) inhibitors, fibric acidderivatives, squalene synthetase inhibitors and other known cholesterollowering agents, lipoxygenase inhibitors, ACAT inhibitors, and PPAR α/γdual agonists as disclosed hereinafter.

BRIEF DESCRIPTION OF FIGURE

[0015] The accompanying FIGURE is a computer generated image of apartial X-ray structure of compound XVIA (described hereinafter) boundto human aP2.

DETAILED DESCRIPTION OF THE INVENTION

[0016] Examples of aP2 inhibitors suitable for use herein includecompounds which include an oxazole or analogous ring. Thus, U.S. Pat.No. 5,218,124 to Failli et al (the disclosure of which is incorporatedherein by reference) discloses compounds, which have activity as aP2inhibitors and thus suitable for use herein, which include substitutedbenzoylbenzene, bipheny- and 2-oxazole-alkanoic acid derivatives havingthe following structure:

A(CH₂)_(n)O—B  I

[0017] wherein

[0018] A is a group having the formula

[0019] wherein

[0020] X is —N— or

[0021] Z is

[0022] —S— or —O—

[0023] R¹ is hydrogen lower alkyl or phenyl;

[0024] R² is hydrogen or lower alkyl; or

[0025] R¹ and R² taken together form a benzene ring, with

[0026] the proviso that when X is —N—, Z is other than

[0027] R³ is hydrogen or lower alkyl;

[0028] n is 1-2;

[0029] B is

[0030] wherein

[0031] Y is OR⁵ or N(OH)R⁸;

[0032] R⁴ and R⁵ are each, independently, hydrogen or lower alkyl;

[0033] R⁶ is hydrogen, halo or nitro;

[0034] R⁷ is

[0035] R⁸ is lower alkyl;

[0036] m is 0-3;

[0037] and the pharmacologically acceptable salts thereof.

[0038] The grouping A embraces, inter alia, 5- or 6-membered unsaturatednitrogen, sulfur or oxygen containing mono- or benzofused-heterocycles,optionally substituted with lower alkyl or phenyl. The foregoingdefinition embraces the following heterocyclic moieties; furyl,pyrrolyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridyl, pyrazinyl,pyrimidinyl, benzofuranyl, benzothienyl, benzothiazolyl, indolyl,benzoxazolyl, quinazolinyl, benzimidazolyl, quinoxalinyl, quinazolinyland the like.

[0039] Preferred are the examples where A is defined as above and B is

[0040] and R⁷ is

[0041] In another embodiment of the present invention, compounds whichhave activity as aP2 inhibitors suitable for use herein are disclosed inU.S. Pat. No. 5,403,852 to Barreau et al (which is incorporated hereinby reference) which are oxazole derivatives and have the structure

[0042] in which;

[0043] R and R′ are identical or different and represent a hydrogen atomor an alkyl radical containing 1 or 2 carbon atoms,

[0044] R₁ and R₂ are identical or different and represent hydrogen orhalogen atoms or alkyloxy radicals in which the alkyl portion contains 1to 4 carbon atoms in a straight or branched chain, and

[0045] n equals 3 to 6,

[0046] as well to their salts, to their isomers where they exist and topharmaceutical compositions containing them.

[0047] In addition, other compounds which have activity as aP2inhibitors suitable for use in the method of the invention are compoundsdisclosed in U.S. Pat. No. 4,001,228 to Mattalia (which is incorporatedherein by reference) which are 2-thiol-4,5-diphenyloxazole S-derivativeswhich have the structure

[0048] wherein m is 0, 1 or 2, n is 1 and R represents hydroxy, alkoxyor amino. Also included within the scope of this invention are salts ofthe compounds of formula III above, particularly pharmaceuticallyacceptable addition salts thereof.

[0049] Preferred are S-(4,5-diphenyloxazol-2-yl)-mercaptocarboxylicacids of the formula:

[0050] wherein m is 0, 1 or 2, and pharmaceutically acceptable loweralkyl esters and salts thereof.

[0051] In another embodiment of the present invention, compounds whichhave activity as aP2 inhibitors suitable for use herein are disclosed inU.S. Pat. No. 4,051,250 to Dahm et al (the disclosure of which isincorporated herein by reference) which discloses azole derivatives ofthe structure

[0052] wherein R₁ is carboxyl, esterified carboxyl or other functionallymodified carboxyl group; R₂ and R₃ each are aryl of up to 10 carbonatoms; A is C_(n)H_(2n) in which n is an integer from 1 to 10,inclusive; and Z is O or S, and the physiologically acceptable saltsthereof.

[0053] Preferred are preferred compounds as disclosed in the Dahm et alpatent.

[0054] In still another embodiment of the invention, compounds whichhave activity as aP2 inhibitors suitable for ue herein are disclosed inU.S. Pat. No. 5,380,854 to Romine et al (the disclosure of which isincorporated herein by reference) and are phenyl-heterocyclic oxazolederivatives which have the structure

[0055] R is CH₂R²;

[0056] R¹ is Ph or Th;

[0057] R² is

[0058] CO₂R³, and

[0059] R³ is H, or C₁-C₄ lower alkyl;

[0060] or pharmaceutically acceptable salt thereof.

[0061] Preferred are the compounds where R is CH₂CO₂H and

[0062] or its tautomer and R¹ is Ph.

[0063] In yet another embodiment of the method of the invention,compounds which have activity as aP2 inhibitors suitable for use hereinare disclosed in PCT application WO 95/17393 which are diaryloxazolederivatives having the structure

[0064] wherein R¹ is carboxy or protected carboxy,

[0065] R² is aryl which may have suitable substituent(s),

[0066] R³ is aryl which may have suitable substituent(s),

[0067] A¹ is lower alkylene,

[0068] A² is bond or lower alkylene and

[0069] -Q- is

[0070] (in which

[0071] is cyclo (lower)alkane or cycle(lower)alkene, each of which mayhave suitable substituent(s)).

[0072] Preferred are the preferred compounds of WO 95/17393 asillustrated by the working Examples thereof.

[0073] Another embodiment of compounds which have activity as aP2inhibitors suitable for use herein are disclosed in U.S. Pat. No.5,362,879 to Meanwell (the disclosure of which is incorporated herein byreference) which are 4,5-diphenyloxazole derivatives having thestructures

[0074] wherein

[0075] R is H or C₁-C₅ lower alkyl,

[0076] X is N or CH,

[0077] Y is H or CO₂R¹, or COR²,

[0078] R¹ is C₁-C₅ lower alkyl, or phenylmethyl, and

[0079] R² is C₁-C₅ alkyl;

[0080] wherein

[0081] R is H or C₁-C₅ lower alkyl,

[0082] X is (CH₂)_(n) or para or meta substituted phenyl wherein thesubstituent is OR²,

[0083] R² is C₁-C₅ alkyl, and

[0084] n is an integer of 4 to 8,

[0085] and pharmaceutically acceptable salts thereof.

[0086] Preferred are the preferred compounds of the Meanwell patent asillustrated by the working Examples thereof.

[0087] In still another embodiment of the present invention, compoundswhich have activity as aP2 inhibitors suitable for use herein aredisclosed in U.S. Pat. No. 5,187,188 to Meanwell (the disclosure ofwhich is incorporated herein by reference) which are oxazole carboxylicacid derivatives having the structure

[0088] wherein

[0089] Y and Z are independently hydrogen or together form a bond;

[0090] X is CN, CO₂R¹ or CONR²R³;

[0091] R and R¹ are independently or together H, Na, or C₁-C₅ loweralkyl;

[0092] R² and R³ are independently or together H, or C₁-C₅ lower alkyl;

[0093] or alkali metal salt thereof.

[0094] Preferred are the preferred compounds of the above Meanwellpatent as illustrated by the working Examples thereof.

[0095] In another embodiment of the invention, compounds which haveactivity as aP2 inhibitors suitable for use herein are disclosed in U.S.Pat. No. 5,348,969 to Romine et al (the disclosure of which isincorporated herein by reference) which are phenyloxazolyloxazolederivatives having the structure

[0096] wherein

[0097] x is

[0098] Y is C₃, Ph, or OH, provided that when Y is OH, the compoundexists an the kero-enol tautaumerism form

[0099] R¹ is Ph or Th;

[0100] R² is CH₂R³;

[0101] R³ is CO₂R⁴;

[0102] R⁴ is H or C₁-C₅ lower alkyl;

[0103] R⁵ is H or CH₃; R⁶ is OHCHN or H₂N; and

[0104] R⁷ is H or OH;

[0105] or pharmaceutically acceptable salt thereof.

[0106] Preferred are the preferred compounds as delineated in the Romineet al patent and in the working Examples thereof, especially where X is

[0107] and R² is CH₂CO₂H.

[0108] In addition, compounds which have activity as aP2 inhibitorswhich may be employed herein include those disclosed in U.S. Pat. No.5,262,540 to Meanwell (the disclosure of which is incorporated herein byreference) and are 2-(4,5-diaryl)-2-oxazolyl substituted phenoxyalkanoicacids and esters having the structre

[0109] (wherein n is 7-9 and R is hydrogen or lower alkyl; or when R ishydrogen, the alkali metal salt thereof),

[0110] wherein

[0111] R₁ is phenyl or thienyl;

[0112] R₂ is hydrogen, lower alkyl or together with CO₂ istetrazol-1-yl;

[0113] X is a divalent connecting group selected from the groupconsisting of CH₂CH₂, CH═CH, and CH₂O;

[0114] Y is a divalent connecting group attached to the 3- or 4-phenylposition selected from the group consisting of OCH₂, CH₂CH₂ and CH═CH,

[0115] or when R₂ is hydrogen, an alkali metal salt thereof.

[0116] Preferred are the preferred compounds as set out in the aboveMeanwell et al patent as illustrated in the working Examples thereof.

[0117] In another embodiment of the invention, compounds which haveactivity as aP2 inhibitors suitable for use herein are disclosed in PCTapplication WO 92/04334 which are substituted 4,5-diaryl heterocycleshaving the formula

[0118] in which

[0119] each group Ar is the same or different and is optionallysubstituted phenyl or optionally substituted heteroaryl;

[0120] X is nitrogen or CR¹;

[0121] Y is nitrogen, N(CH₂)_(n)A or C(CH₂)_(n)A;

[0122] Z is nitrogen, oxygen or N(CH₂)_(n)A, and the dotted lineindicates the optional presence of a double bond so as to form a fullyunsaturated heterocyclic ring;

[0123] R¹ is hydrogen, C₁₋₄alkyl, optionally substituted phenyl oroptionally substituted heteroaryl;

[0124] n is 4 to 12; and

[0125] A is CO₂H or a group hydrolysable to CO₂H, 5-tetrazolyl, SO₃H,P(O) (OR)₂, P(O) (OH)₂, or P(O) (R) (OR) in which R is hydrogen orC₁₋₄alkyl, or a pharmaceutically acceptable salt thereof.

[0126] Preferred are preferred compounds of WO 92/04334.

[0127] In yet another embodiment of the invention, compounds which haveactivity as aP2 inhibitors suitable for use herein are disclosed inFrench Patent 2156486 which have the structure

[0128] Where X is O or S;

[0129] R₁ is H, phenyl or phenyl substituted with F, Cl or Br or alkoxy,

[0130] R₂ is H, alkyl, phenyl or phenyl substituted with F, Cl or Br oralkoxy, and

[0131] R₃ is H or alkyl.

[0132] Preferred are those preferred compounds as set out in FrenchPatent No. 2156486.

[0133] Most preferred oxazole compounds as aP2 inhibitors are thecompounds

[0134] which may be prepared as disclosed in U.S. Pat. No. 5,348,969 toRomine et al.

[0135] Another class of aP2 inhibitors suitable for use in the method ofthe invention include pyrimidine derivatives. Thus, U.S. Pat. No.5,599,770 to Kubota et al (the disclosure of which is incorporatedherein by reference) disclose compounds which have activity as aP2inhibitors and thus suitable for use herein include2-benzyloxypyrimidine derivatives having the following structure

[0136] wherein

[0137] R¹ and R² are each independently H, a halogen, hydroxyl, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₃-C₅ alkenyl, C₃-C₅ alkynyl, C₁-C₄ alkoxy,C₁-C₄ haloalkoxy, C₃-C₅ alkenyloxy, C₃-C₅ alkynyloxy, C₁-C₄ alkylthio,or phenyl, with the proviso that at least one of R¹ and R² must-behydroxyl;

[0138] n is an integer of 0 to 5; and

[0139] each X which may be identical or different if n is greater than1, is a halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄alkylthio, C₇-C₉ aralkyloxy, phenyl, hydroxymethyl, hydroxycarbonyl,C₁-C₄ alkoxycarbonyl, or nitro.

[0140] Preferred are the compounds in which either R¹ or R² is hydroxyland the other R¹ or R² is C₁-C₄ alkyl and X is halogen.

[0141] In another embodiment of the method of the invention, compoundswhich have activity as aP2 inhibitors suitable for use herein aredisclosed in A. Mai et al “Dihydro(alkylthio)-(naphthylmethyl)oxopyrimidines: Novel Non-Nucleoside ReverseTranscriptase Inhibitors of the S-DABO. Series”, J. Med. Chem., 1997,40, 1447-1454 which have the structures

[0142] R¹=sec-butyl, cyclopentyl, cyclohexyl;

[0143] R²═H, CH₃. The structures XIVA-XIVE are depicted in their ketoform. However, it will be apparent to one skilled in the art that theymay also exist in their enol form to give structures of the type

[0144] In yet another embodiment of the method of the invention,compounds which have activity as aP2 inhibitors suitable for use hereinare disclosed in PCT application WO 96/35678 which are α-substitutedpyrimidine-thioalkyl and alkylether compounds which have the structure

[0145] where m is 0 or 1;

[0146] R¹ is selected from —CO₂R₅₃, —CONR₅₄R₅₅,

[0147] where s is 0 or 1, and R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, and R₂₅ are thesame or different and are selected from —H, C₁-C₆ alkyl, C₁-C₆ alkenyl,C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₃-C₈ cycloalkyl, —CF₃, —NO₂, -halo, —OH,—CN, phenyl, phenylthio, -styryl, —CO₂(R₃₁), —CON(R₃₁) (R₃₂), —CO(R₃₁),—(CH₂)_(n)—N(R₃₁) (R₃₂), —C(OH) (R₃₁(R₃₃), —(CH₂)_(n)N(R₃₁) (CO(R₃₃)),(CH₂)_(n)N(R₃₁) (SO₂ (R₃₃)), or where R₂₀ and R₂₁, or R₂₁ and R₂₂, orR₂₂ and R₂₃ are taken together to form a five or six-membered saturatedor unsaturated ring containing 0 or 1 oxygen, nitrogen or sulfur, wherethe unsaturated ring may be optionally substituted with 1, 2 or 3, C₁-C₆alkyl, C₁-C₆ alkoxy, —OH, —CH₂OH, —(CH₂)_(n)—N(R₃₁)(R₃₂), —C₃-C₈cycloalkyl, —CF₃, -halo, CO₂(R₃₁), —CON(R₃₁)(R₃₂), —CO(R₃₁),—(CH₂)_(n)N(R₃₁) (CO(R₃₃)), —(CH₂)_(n)N(R₃₁) (SO₂ (R₃₃)), —CN, —CH₂CF₃or —CH(CF₃)₂, or phenyl and the saturated ring may be optionallysubstituted with 1, 2 or 3, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, —OH, —CH₂OH or—(CH₂)_(n)—N(R₃₁)(R₃₂) or one oxo (═O);

[0148] where n is 0-3 and R₃₁, R₃₂ and R₃₃ are the same or different andare selected from

[0149] —H,

[0150] C₁-C₆ alkyl,

[0151] phenyl optionally substituted with 1, 2 or 3-halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, —CF₃, —OH or —CN,

[0152] or where R₃₁ and R₃₂ taken together with the attached nitrogen toform a ring selected from -pyrrolidinyl, -piperidinyl, -4-morpholinyl,-4-thiomorpholinyl, -4-piperazinyl, -4-(1-C₁-C₆alkyl)piperazinyl, or amember selected from:

[0153] 1-cyclohexenyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,2-imidazolyl, 4-imidazolyl, 2-benzothiazolyl, 2-benzoxazolyl,2-benzimidazolyl, 2-oxazolyl, 4-oxazolyl, 2-thiazolyl, 3-isoxazolyl,5-isoxazolyl, 5-methyl-3-isoxazolyl, 5-phenyl-3-isoxazolyl, 4-thiazolyl,3-methyl-2-pyrazinyl, 5-methyl-2-pyrazinyl, 6-methyl-2-pyrazinyl,5-chloro-2-thienyl, 3-furyl, benzofuran-2-yl, benzothien-2-yl,2H-1-benzopyran-3-yl, 2,3-dihydrobenzopyran-5-yl, 1-methylimidazol-2-yl,quinoxalin-2-yl, piperon-5-yl, 4,7-dichlorobenzoxazol-2-yl,4,6-dimethylpyrimidin-2-yl, 4-methylpyrimidin-2-yl,2,4-dimethylpyrimidin-6-yl, 2-methylpyrimidin-4-yl,4-methylpyrimidin-6-yl, 6-chloropiperon-5-yl,5-chloroimidazol[1,2-a]pyridin-2-yl, 1-H-inden-3-yl,1-H-2-methyl-inden-2-yl, 3,4-dihydronaphth-1-yl,S-4-isopropenylcyclohexen-1-yl or 4-dihydronaphth-2-yl;

[0154] where R₅₃ is selected from —H, C₁-C₆alkyl, C₃-C₆cycloalkyl,phenyl (optionally substituted with 1,2, or 3-halo, C₁-C₆ alkyl, C₁-C₆alkoxy, —CF₃, —OH, —CN), or a five or six-membered unsaturated ringcontaining 0 or 1 oxygen, nitrogen or sulfur, where the unsaturated ringmay be optionally substituted with —H, C₁-C₆ alkyl, C₁-C₆ alkoxy, —OH,—CH₂OH, or —(CH₂)_(n)—N(R₃₁)(R₃₂);

[0155] where R₅₄ and R₅₅ being the same or different are selected from—H, C₁-C₆ alkyl, allyl, or phenyl (optionally substituted with 1, 2 or3-halo, C₁-C₆ alkyl, C₁-C₆ alkoxy or —CF₃), or taken together with theattached nitrogen to form a ring selected from -pyrrolidinyl,-piperidinyl, -4-morpholinyl, -4-thiomorpholinyl, -4-piperazinyl,-4-(1-C₁-C₆alkyl)piperazinyl;

[0156] R₄₁ and R₄₂, being the same or different, are selected from —Hand C₁-C₄ alkyl;

[0157] R₁₂ is selected from —H, C₁-C₆ alkyl, —C₃-C₆ cycloalkyl, —CN,—C(O)NH₂, —C(O)N(C₁-C₆alkyl) (C₁-C₆alkyl), —CO₂H, —CO₂(C₁-C₆alkyl),—CH₂OH, —CH₂NH₂ or —CF₃;

[0158] R₁₃ is selected from —H, C₁-C₆ alkyl or —CF₃;

[0159] Y is selected from —S—, —S(O)—, —S(O)₂, or —O—;

[0160] R₄ is —OH;

[0161] R₅ is selected from —H, —C₂H₄OH, —C₂H₄—O-TBDMS, halo, —C₃-C₆cycloalkyl, C₁-C₃ alkoxy, —CH₂CH₂C₁ or C₁-C₄ alkyl, with the provisothat R₅ is not isobutyl;

[0162] or, when R₆ is hydroxyl, R₄ and R₅ are taken together to form afive or six-memebered saturated or unsaturated ring which together withthe pyrimidine ring form the group consisting of7H-pyrrolo[2,3-d]pyrimidine, 5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidine,furo[2,3-d]pyrimidine, 5,6-dihydro-furo[2,3-d]pyrimidine,thieno[2,3-d]pyrimidine, 5,6-dihydro-thieno[2,3-d]pyrimidine,1H-pyrazolo[3,4-d]pyrimidine, 1H-purine, pyrimido[4,5-d]pyrimidine,pteridine, pyrido[2,3-d]pyrimidine, or quinazoline, where theunsaturated ring may be optionally substituted with 1, 2 or 3, C₁-C₆alkyl C₁-C₆ alkoxy, —OH, —CH₂OH, or —(CH₂) n—N(R₃₁) (R₃₂), —C₃-C₈cycloalkyl, —CF₃, -halo, —CO₂(R₃₁)_(n)—CON(R₃₁) (R₃₂), —CO(R₃₁),—(CH₂)_(n)N(R₃₁) (CO(R₃₃)), —(CH₂)_(n)N(R₃₁) (SO₂ (R₃₃)), and thesaturated ring may be optionally substituted with 1, 2 or 3, —C₁-C₆alkyl, C₁-C₆ alkoxy, —OH, —CH₂OH, or —(CH₂)_(n)N(R₃₁) (R₃₂) or one oxo(═O); and

[0163] R₆ is selected from —H, —OH, halo, —CN, —CF₃, —CO₂(R₆₁), —C(O)R₆₁or —C(O)N(R₆₁) (R₆₂) where R₆₁ and R₆₂ are the same or different and areselected from

[0164] —H,

[0165] C₁-C₆ alkyl,

[0166] phenyl optionally substituted with 1, 2 or 3-halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, —CF₃, —OH, —CN,

[0167] or where R₆₁ and R₆₂ taken together with the attached nitrogen toform a ring selected from -pyrrolidinyl, -piperidinyl, -4-morpholinyl,-4-thiomorpholinyl, -4-piperazinyl, or -4-(C₁-C₆ alkyl)piperazinyl; or

[0168] pharmaceutically acceptable salts, hydrates, N-oxides andsolvates thereof.

[0169] A preferred embodiment is pyrimidine-thioalkyl and alkylether,where

[0170] R₄ is —OH; and

[0171] R₆ is selected from —H, halo, —CN, —CF₃, —CO₂(R₁₆), —C(O)R₆₁ or—C(O)N(R₆₁)(R₆₂), preferably CF₃.

[0172] A preferred embodiment are compounds of Formula XVI where s is 0or 1, and Y is —S— or O; more preferably Y is —S—.

[0173] Preferred are pyrimidine derivatives of the structures

[0174] which may be prepared as disclosed in WO 96/35678.

[0175] Another embodiment of the method of the invention includes use ofaP2 inhibitors which are pyridazinone derivatives. French Patent No.2,647,676 discloses compounds which have activity as aP2 inhibitors andthus suitable for use herein which have the structures

[0176] where R₁ and R₂ are H, alkyl, aryl or arylalkyl, where the alkylcan include as substituents halogen, CF₃, CH₃O, CH₃S, NO₂, or R₁ and R₂with the carbons to which they are attached can form methylenedioxy, or

[0177] R₁ and R₂ can form a C₃-C₇ non-aromatic ring, or a heterocyclewhich can be pyridine, pyrazine, pyrimidine, pyridazine, indol, orpyrazole, or an oxygen containing heterocycle which can be pyran orfuran, or a sulfur containing heterocycle which can be thiopyran, orthiophene; the heterocycles being optionally substituted with halogen oralkyl,

[0178] R₃ and R₄ are H, alkyl, halogen, CF₃, CH₃O, CH₃S or NO₂ or R₃ andR₄ with the carbons to which they are attached can form a methylenedioxygroup,

[0179] R₅ is H, and

[0180] Z is a heterocycle which can be pyridine, thiazole,benzothiazole, benzimidazole or quinoline, which Z group can optionallybe substituted with halogen or alkyl.

[0181] The preferred pyridazinone derivative is

[0182] which may be prepared as disclosed in French Patent No.2,647,676.

[0183] Preferred aP2 inhibitors for use herein will include an oxazolering.

[0184] Unless otherwise indicated, the term “lower alkyl”, “alkyl” or“alk” as employed herein alone or as part of another group includes bothstraight and branched chain hydrocarbons, containing 1 to 40 carbons,preferably 1 to 20 carbons, more preferably 1 to 12 carbons, in thenormal chain, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl,isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethyl-pentyl, nonyl, decyl, undecyl, dodecyl, the variousbranched chain isomers thereof, and the like as well as such groupsincluding 1 to 4 substituents such as halo, for example F, Br, Cl or Ior CF₃, alkoxy, aryl, aryloxy, aryl(aryl) or diaryl, arylalkyl,arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy,amino, hydroxy, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl,heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, alkylamido, alkanoylamino,arylcarbonylamino, nitro, cyano, thiol, haloalkyl, trihaloalkyl and/oralkylthio.

[0185] Unless otherwise indicated, the term “cycloalkyl” as employedherein alone or as part of another group includes saturated or partiallyunsaturated (containing or 2 double bonds) cyclic hydrocarbon groupscontaining 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl andtricyclicalkyl, containing a total of 3 to 20 carbons forming the rings,preferably 4 to 12 carbons, forming the ring and which may be fused to 1or 2 aromatic rings as described for aryl, which include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyland cyclododecyl, cyclohexenyl,

[0186] any of which groups may be optionally substituted with 1 to 4substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy,arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl,arylcarbonylamino, amino, nitro, cyano, thiol and/or alkylthio.

[0187] Unless otherwise indicated the term “aryl” or “Ar” as employedherein alone or as part of another group refers to monocyclic andbicyclic aromatic groups containing 6 to 10 carbons in the ring portion(such as phenyl or naphthyl) and may optionally include one to threeadditional rings fused to Ar (such as aryl, cycloalkyl, heteroaryl orcycloheteroalkyl rings) and may be optionally substituted throughavailable carbon atoms with 1, 2, 3 or 4 groups selected from hydrogen,halo, haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl,trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkylalkyl,cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl,aryloxy, aryloxyalkyl, arylalkoxy, arylthio, arylazo, heteroarylalkyl,heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro,cyano, amino, substituted amino wherein the amino includes 1 or 2substituents (which are alkyl, aryl or any of the other aryl compoundsmentioned in the definitions), thiol, alkylthio, arylthio,heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl,arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl,aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino,arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino orarylsulfonaminocarbonyl.

[0188] Unless otherwise indicated the term “aralkyl”, “aryl-alkyl” or“aryllower alkyl” as used herein alone or as part of another grouprefers to alkyl groups as discussed above having an aryl substituent,such as benzyl or phenethyl, or naphthylpropyl, or an aryl as definedabove.

[0189] Unless otherwise indicated, the term “cycloheteroalkyl” as usedherein alone or as part of another group refers to a 5-, 6- or7-membered saturated or partially unsaturated ring which includes 1 to 2hetero atoms such as nitrogen, oxygen and/or sulfur, linked through acarbon atom or a heteroatom, where possible, optionally via the linker(CH₂). (where p is 1, 2 or 3), such as

[0190] and the like. The above groups may include 1 to 3 substituentssuch as any of the substituents for alkyl or aryl as defined above. Inaddition, any of the above rings can be fused to 1 or 2 cycloalkyl,aryl, heteroaryl or cycloheteroalkyl rings.

[0191] Unless otherwise indicated, the term “heteroaryl” (also referredto as heteroaryl) as used herein alone or as part of another grouprefers to a 5- or 6-membered aromatic ring which includes 1, 2, 3 or 4hetero atoms such as nitrogen, oxygen or sulfur, and such rings fused toan aryl, cycloalkyl, heteroaryl or cycloheteroalkyl ring (e.g.benzothiophenyl, indolyl), linked through a carbon atom or a heteroatom,where possible, optionally via the linker (CH₂)_(p) (which is definedabove), such as

[0192] and the like.

[0193] The heteroaryl groups including the above groups may optionallyinclude 1 to 4 substituents such as any of the substituents listed foraryl. In addition, any of the above rings can be fused to a cycloalkyl,aryl, heteroaryl or cycloheteroalkyl ring.

[0194] The term “prodrug esters” as employed herein includes prodrugesters which are known in the art for both phosphorus and carboxylicacids such as similar carboxylic acid esters such as methyl, ethylbenzyl and the like. Other examples include the following groups:(1-alkanoyloxy)alkyl such as,

[0195] wherein R^(a), R^(b) and R^(c) are H, alkyl, aryl or aryl-alkyl;however R^(a)O cannot be HO. Examples of such prodrug esters include

[0196] Other examples of suitable prodrug esters include

[0197] wherein R^(a) can be H, alkyl (such as methyl or t-butyl),arylalkyl (such as benzyl) or aryl (such as phenyl); R^(d) is H, alkyl,halogen or alkoxy, R^(e) is alkyl, aryl, arylalkyl or alkoxyl, and n₁ is0, 1 or 2; or

[0198] (d is 0 to 3)

[0199] Where the aP2 inhibitor is in acid form it may form apharmaceutically acceptable salt such as alkali metal salts such aslithium, sodium or potassium, alkaline earth metal salts such as calciumor magnesium as well as zinc or aluminum and other cations such asammonium, choline, diethanolamine, ethylenediamine, t-butylamine,t-octylamine, dehydroabietylamine.

[0200] Where desired, the aP2 inhibitor may be used in combination withanother antiatherosclerotic agent which may be administered orally inthe same dosage form in accordance with the invention, a separate oraldosage form or by injection.

[0201] It is believed that the use of the aP2 inhibitor in combinationwith another antiatherosclerotic agent produces antiatheroscleroticresults greater than that possible from each of these medicaments aloneand greater than the combined additive antiatherosclerotic effectsproduced by these medicaments.

[0202] The other antiatherosclerotic agent employed in the methods ofthe invention include MTP inhibitors disclosed in in U.S. Pat. No.5,595,872, U.S. Pat. No. 5,739,135, U.S. Pat. No. 5,712,279, U.S. Pat.No. 5,760,246, U.S. Pat. No. 5,827,875, U.S. Pat. No. 5,885,983 and U.S.application Ser. No. 09/175,180 filed Oct. 20, 1998, now U.S. Pat. No.______. Preferred are each of the preferred MTP inhibitors disclosed ineach of the above patents and applications.

[0203] All of the above U.S. Patents and applications are incorporatedherein by reference.

[0204] Most preferred MTP inhibitors to be employed in accordance withthe present invention include preferred MTP inhibitors as set out inU.S. Pat. Nos. 5,739,135 and 5,712,279, and U.S. Pat. No. 5,760,246.

[0205] Thus, preferred compounds in U.S. Pat. Nos. 5,739,135 and5,712,279 for use herein are compounds of the structure

[0206] where Z is a bond;

[0207] X¹ and X² are H;

[0208] R⁵ is aryl such as phenyl substituted with

[0209] (1) aryl such as phenyl,

[0210] (2) heteroaryl such as

[0211] (3) halo such as Cl

[0212] R⁵ is heteroaryl such as

[0213] substituted with

[0214] (1) aroyl such as

[0215] (2) arylthio such as

[0216] wherein the R⁵ substituent is preferably in the position adjacentto the carbon linked to

[0217] (CH₂)_(x) is —(CH₂)₄— or

[0218] Most preferred is

[0219]9-14-[4-[[2-(2,2,2-Trifluoroethoxy)benzoyl)amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide

[0220] Preferred compounds in U.S. Pat. No. 5,760,246 for use herein areMTP inhibitor compounds which have the formula

[0221] wherein A is NH,

[0222] B is

[0223] X is a bond, oxygen or sulfur; R³ and R⁴ are independently H orF.

[0224] Preferred R¹ groups are aryl, preferably phenyl, heteroaryl,preferably imidazoyl or pyridyl (preferably substituted with one of thepreferred R¹ substituents: arylcarbonylamino, heteroarylcarbonyl-amino,cycloalkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroaryl-sulfonylamino), PO(OAlkyl)₂,heteroarylthio, benzthiazole-2-thio, imidazole-2-thio, alkyl, oralkenyl, cycloalkyl such as cyclohexyl, or 1,3-dioxan-2-yl.

[0225] Preferred R² groups are alkyl, polyfluoroalkyl (such as1,1,1-trifluoroethyl), alkenyl, aryl or heteroaryl (preferablysubstituted with one of the preferred R¹ substituents above), orPO(OAlkyl)₂.

[0226] If R² is alkyl, 1,1,1-trifluoroethyl, or alkenyl, it is preferredthat R¹ is other than alkyl or alkenyl.

[0227] It is preferred that L¹ contains 1 to 5 atoms in the linear chainand L² is a bond or lower alkylene.

[0228] Most preferred is

[0229] The other antiatherosclerotic agent may be an HMG CoA reductaseinhibitor which includes, but is not limited to, mevastatin and relatedcompounds as disclosed in U.S. Pat. No. 3,983,140, lovastatin(mevinolin) and related compounds as disclosed in U.S. Pat. No.4,231,938, pravastatin and related compounds such as disclosed in U.S.Pat. No. 4,346,227, simvastatin and related compounds as disclosed inU.S. Pat. Nos. 4,448,784 and 4,450,171, with pravastatin, lovastatin orsimvastatin being preferred. Other HMG CoA reductase inhibitors whichmay be employed herein include, but are not limited to, fluvastatin,disclosed in U.S. Pat. No. 5,354,772, cerivastatin disclosed in U.S.Pat. Nos. 5,006,530 and 5,177,080, atorvastatin disclosed in U.S. Pat.Nos. 4,681,893, 5,273,995, 5,385,929 and 5,686,104, pyrazole analogs ofmevalonolactone derivatives as disclosed in U.S. Pat. No. 4,613,610,indene analogs of mevalonolactone derivatives as disclosed in PCTapplication WO 86/03488,6-(2-(substituted-pyrrol-1-yl)-alkyl)pyran-2-ones and derivativesthereof as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355 (a3-substituted pentanedioic acid derivative) dichloroacetate, imidazoleanalogs of mevalonolactone as disclosed in PCT application WO 86/07054,3-carboxy-2-hydroxy-propane-phosphonic acid derivatives as disclosed inFrench Patent No. 2,596,393, 2,3-disubstituted pyrrole, furan andthiophene derivatives as disclosed in European Patent Application No.0221025, naphthyl analogs of mevalonolactone as disclosed in U.S. Pat.No. 4,686,237, octahydronaphthalenes such as disclosed in U.S. Pat. No.4,499,289, keto analogs of mevinolin (lovastatin) as disclosed inEuropean Patent Application No.0,142,146 A2, as well as other known HMGCoA reductase inhibitors.

[0230] In addition, phosphinic acid compounds useful in inhibiting HMGCoA reductase suitable for use herein are disclosed in GB 2205837.

[0231] The squalene synthetase inhibitors suitable for use hereininclude, but are not limited to, α-phosphono-sulfonates disclosed inU.S. Pat. No. 5,712,396, those disclosed by Biller et al, J. Med. Chem.,1988, Vol. 31, No. 10, pp 1869-1871, including isoprenoid(phosphinylmethyl)phosphonates as well as other squalene synthetaseinhibitors as disclosed in U.S. Pat. Nos. 4,871,721 and 4,924,024.

[0232] In addition, other squalene synthetase inhibitors suitable foruse herein include the terpenoid pyrophosphates disclosed by P. Ortiz deMontellano et al, J. Med. Chem., 1977, 20, 243-249, the farnesyldiphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs asdisclosed by Corey and Volante, J. Am.

[0233] Chem. Soc., 1976, 98, 1291-1293, phosphinylphosphonates reportedby McClard, R. W. et al, J.A.C.S., 1987, 109, 5544 and cyclopropanesreported by Capson, T. L., PhD dissertation, June 1987, Dept. Med. Chem.U of Utah, abstract, Table of Contents, pp 16, 17, 40-43, 48-51,

SUMMARY

[0234] Preferred are pravastatin, lovastatin, simvastatin, atorvastatin,fluvastatin and cerivastatin.

[0235] All of the above U.S. applications are incorporated herein byreference.

[0236] Other cholesterol lowering drugs suitable for use herein include,but are not limited to, antihyperlipoproteinemic agents such as fibricacid derivatives, such as fenofibrate, gemfibrozil, clofibrate,bezafibrate, ciprofibrate, clinofibrate and the like, probucol, andrelated compounds as disclosed in U.S. Pat. No. 3,674,836, probucol andgemfibrozil being preferred bile acid sequestrants such ascholestyramine, colestipol and DEAE-Sephadex (Secholex®, Polidexide®),as well as clofibrate, lipostabil (Rhone-Poulenc), Eisal E-5050 (anN-substituted ethanolamine derivatives, imanixii (HOE-402),tetrahydrolipstatin (THL), istigmastanylphosphorylcholine (SPC, troche),aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulenederivative), melinamide (Sumitomo), Sandoz 58-035. American CyanamidCL-277,082 and CL-283,546 (disubstituted urea derivatives), nicotinicacid, acipimox, acifran, neomycin, p-aminosalicylic acid, aspirin,poly(diallylmethylamine) derivatives such as disclosed in U.S. Pat. No.4,759,923, quaternary amine poly(diallyldimethylarmonium chloride) andionenes such as disclosed in U.S. Pat. No. 4,027,009, and other knownserum cholesterol lowering agents.

[0237] The above-mentioned U.S. patents are incorporated herein byreference.

[0238] The other antiatherosclerotic agent may also be a PPAR α/γ dualagonist such as disclosed by Murakami et al, “A Novel Insulin SensitizerActs As a Coligand for Peroxisome Proliferator—Activated Receptor Alpha(PPAR alpha) and PPAR gamma. Effect on PPAR alpha Activation on AbnormalLipid Metabolism in Liver of Zucker Fatty Rats”, Diabetes 47, 1841-1847(1998).

[0239] The other antiatherosclerotic agent may be an ACAT inhibitor suchas disclosed in, “The ACAT inhibitor, Cl-1011 is effective in theprevention and regression of aortic fatty streak area in hamsters”,Nicolosi et al, Atherosclerosis (Shannon, Irel). (1998), 137(1), 77-85;“The pharmacological profile of FCE 27677: a novel ACAT inhibitor withpotent hypolipidemic activity mediated by selective suppression of thehepatic secretion of ApoB100-containing lipoprotein”, Ghiselli,Giancarlo, Cardiovasc. Drug Rev. (1998), 16(1), 16-30; “RP 73163: abioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitor”, Smith, C.,et al, Bioorg. Med. Chem. Lett. (1996), 6(1), 47-50; “ACAT inhibitors:physiologic mechanisms for hypolipidemic and anti-atheroscleroticactivities in experimental animals”, Krause et al, Editor(s): Ruffolo,Robert R., Jr.; Hollinger, Mannfred A., Inflammation: Mediators Pathways(1995), 173-98, Publisher: CRC, Boca Raton, Fla.; “ACAT inhibitors:potential anti-atherosclerotic agents”, Sliskovic et al, Curr. Med.Chem. (1994), 1(3), 204-25; “Inhibitors of acyl-CoA:cholesterol O-acyltransferase (ACAT) as hypocholesterolemic agents. 6. The firstwater-soluble ACAT inhibitor with lipid-regulating activity. Inhibitorsof acyl-CoA:cholesterol acyltransferase (ACAT). 7. Development of aseries of substituted N-phenyl-N′-[(1-phenylcyclopentyl)methyl]ureaswith enhanced hypocholesterolemic activity”, Stout et al, Chemtracts:Org. Chem. (1995), 8(6), 359-62.

[0240] The other antiatherosclerotic agent may also be a lipoxygenaseinhibitor including a 15-lipoxygenase (15-LO) inhibitor such asbenzimidazole derivatives as disclosed in WO 97/12615, 15-LO inhibitorsas disclosed in WO 97/12613, isothiazolones as disclosed in WO 96/38144,and 15-LO inhibitors as disclosed by Sendobry et al “Attenuation ofdiet-induced atherosclerosis in rabbits with a highly selective15-lipoxygenase inhibitor lacking significant antioxidant properties,Brit. J. Pharmacology (1997) 120, 1199-1206, and Cornicelli et al,“15-Lipoxygenase and its Inhibition: A Novel Therapeutic Target forVascular Disease”, Current Pharmaceutical Design, 1999, 5, 11-20.

[0241] The aP2 inhibitor will be employed in a weight ratio to the otherantiatherosclerotic agent (where present), in accordance with thepresent invention, within the range from about 500:1 to about 1:500,preferably from about 100:1 to about 1:100.

[0242] The dose administered must be carefully adjusted according toage, weight and condition of the patient, as well as the route ofadministration, dosage form and regimen and the desired result.

[0243] The dosages and formulations for the other antiatheroscleroticagents will be as disclosed in the various patents and applicationsdiscussed above.

[0244] The dosages and formulations for the other aniatheroscleroticagent to be employed, where applicable, will be as set out in the latestedition of the Physicians' Desk Reference.

[0245] For oral administration, a satisfactory result may be obtainedemploying the MTP inhibitor in an amount within the range of from about0.01 mg/kg to about 100 mg/kg and preferably from about 0.1 mg/kg toabout 75 mg/kg, one to four times daily.

[0246] A preferred oral dosage form, such as tablets or capsules, willcontain the MTP inhibitor in an amount of from about 1 to about 500 mg,preferably from about 2 to about 400 mg, and more preferably from about5 to about 250 mg, one to four times daily.

[0247] For parenteral administration, the MTP inhibitor will be employedin an amount within the range of from about 0.005 mg/kg to about 10mg/kg and preferably from about 0.005 mg/kg to about 8 mg/kg, one tofour times daily.

[0248] For oral administration, a satisfactory result may be obtainedemploying an HMG CoA reductase inhibitor, for example, pravastatin,lovastatin, simvastatin, atorvastatin, fluvastatin or cerivastatin indosages employed as indicated in the Physician's Desk Reference, such asin an amount within the range of from about 1 to 2000 mg, and preferablyfrom about 4 to about 200 mg.

[0249] The squalene synthetase inhibitor may be employed in dosages inan amount within the range of from about 10 mg to about 2000 mg andpreferably from about 25 mg to about 200 mg.

[0250] A preferred oral dosage form, such as tablets or capsules, willcontain the HMG CoA reductase inhibitor in an amount from about 0.1 toabout 100 mg, preferably from about 5 to about 80 mg, and morepreferably from about 10 to about 40 mg.

[0251] A preferred oral dosage form, such as tablets or capsules willcontain the squalene synthetase inhibitor in an amount of from about 10to about 500 mg, preferably from about 25 to about 200 mg.

[0252] The aP2 inhibitor and other antiatherosclerotic agent may beemployed together in the same oral dosage form or in separate oraldosage forms taken at the same time.

[0253] The compositions described above may be administered in thedosage forms as described above in single or divided doses of one tofour times daily. It may be advisable to start a patient on a low dosecombination and work up gradually to a high dose combination.

[0254] Tablets of various sizes can be prepared, e.g., of about 2 to2000 mg in total weight, containing one or both of the active substancesin the ranges described above, with the remainder being aphysiologically acceptable carrier of other materials according toaccepted pharmaceutical practice. These tablets can, of course, bescored to provide for fractional doses. Gelatin capsules can besimilarly formulated.

[0255] Liquid formulations can also be prepared by dissolving orsuspending one or the combination of active substances in a conventionalliquid vehicle acceptable for pharmaceutical administration so as toprovide the desired dosage in one to four teaspoonsful.

[0256] Such dosage forms can be administered to the patient on a regimenof one to four doses per day.

[0257] According to another modification, in order to more finelyregulate the dosage schedule, the active substances may be administeredseparately in individual dosage units at the same time or carefullycoordinated times. Since blood levels are built up and maintained by aregulated schedule of administration, the same result is achieved by thesimultaneous presence of the two substances. The respective substancescan be individually formulated in separate unit dosage forms in a mannersimilar to that described above.

[0258] The formulations as described above will be administered for aprolonged period, that is, for as long as the atherosclerotic conditionexists. Sustained release forms of such formulations which may providesuch amounts biweekly, weekly, monthly and the like, may also beemployed.

[0259] In carrying out the method of the invention, a pharmaceuticalcomposition will be employed containing at least one aP2 inhibitor withor without an antiatherosclerotic agent in association with apharmaceutical vehicle or diluent. The pharmaceutical composition can beformulated employing conventional solid or liquid vehicles or diluentsand pharmaceutical additives of a type appropriate to the mode ofdesired administration. The compounds can be administered to mammalianspecies including humans, monkeys, dogs, etc. by an oral route, forexample, in the form of tablets, capsules, granules or powders, or theycan be administered by a parenteral route in the form of injectablepreparations. The dose for adults is preferably between 50 and 2,000 mgper day, which can be administered in a single dose or in the form ofindividual doses from 1-4 times per day.

[0260] A typical capsule for oral administration contains aP2 inhibitor(250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture ispassed through a 60 mesh sieve and packed into a No. 1 gelatin capsule.

[0261] A typical injectable preparation is produced by asepticallyplacing 250 mg of aP2 inhibitor into a vial, aseptically freeze-dryingand sealing. For use, the contents of the vial are mixed with 2 mL ofphysiological saline, to produce an injectable preparation.

[0262] Compounds sufficiently satisfying the structural criteriadescribed above may be determined by use of an in vitro assay systemwhich measures the potentiation of inhibition of aP2 by displacement ofa fluorescent substrate from aP2 by the inhibitor. Inhibition constants(Ki values) for the inhibitors may be determined by the method describedbelow:

[0263] Production of purified recombinant human aP2 protein. Recombinanthuman aP2 protein is produced by standard recombinant DNA technology. Inthe typical case, aP2 is produced by heterologous expression in E. colistrain BL21(D53) transformed with pETlla vector containing the fulllength human aP2 cDNA (Baxa, C. A., Sha, R. S., Buelt, M. K., Smith, A.J., Matarese, V., Chinander, L. L., Boundy, K. L., and Bernlohr, D. A.(1989). Human adipocyte lipid-binding protein: purification of theprotein and cloning of its complementary DNA. Biochemistry 28: 8683-8690and Xu, Z., Buelt, M. K.,. Banaszak, L. J., and Bernlohr, D. A. (1991).Expression, purification and crystallization of the adipocyte lipidbinding protein. J. Biol. Chem. 266: 14367-14370). Purification of aP2from E. coli is conducted as described by Xu, yielding essentiallyhomogeneous aP2 protein with molecular weight ˜14600 daltons and free ofendogenous fatty acids. The purified aP2 is capable of binding-up to onemole of free fatty acid per mole protein. The binding and structuralproperties of recombinant aP2 protein were previously shown to beidentical to aP2 protein isolated from adipose tissue.

[0264] In vitro assay of aP2 inhibitors. Inhibitors of aP2 are evaluatedin a homogeneous fluorescent-based competition assay using recombinantaP2 protein and 1,8-anilino-naphthalene-sulfonic acid (1,8-ANS) as assaysubstrate. This competition assay was adapted from generalizedprocedures described previously (Kane, C. D. and Bernlohr, D. A. (1996).A simple assay for intracellular lipid-binding proteins usingdisplacement of 1-anilino-8-sulfonic acid. (1996) Anal. Biochem. 233:197-204 and Kurian E., Kirk, W. R. and Prendergast, F. G. (1996)Affinity of fatty acid for r-rat intestinal fatty acid binding protein.Biochemistry, 35, 3865-3874). The method relies on the increase influorescence quantum yield of 1,8-ANS upon binding to the fatty acidbinding site of aP2. The assay is run using appropriate concentrationsof inhibitor, 1,8-ANS, and aP2 protein, in order to calculate theinhibitor binding constant (Ki) for compounds being evaluated. The Kicalculation was based on the procedure previously described forcalculation of dissociation constants described by Kurian. Lower Kivalues indicate higher affinities of compounds binding to aP2.

[0265] In the assay as conducted for the inhibitors described herein, aseries of aliquots of aP2 (5 μM) in solution in 10 mM potassiumphosphate buffer (pH 7.0) are mixed with an equimolar concentration oftest compound, followed by the addition of a series of increasingconcentrations of 1,8-ANS (from 0 to 5 μM). The assay typically isconducted in 96-well plate format with reagents added using roboticinstrumentation (Packard Multiprobe 104). The fluorescence value foreach test is determined using a Cytofluor-4000 multi-well fluorescenceplate reader (Perceptive Biosystems) using excitation wavelength 360 nmand emission wavelength 460 nm, or using other suitablespectrofluorometer. In preparation for the assay, test compounds areinitially prepared at 10 mM in dimethylsulfoxide. All subsequentdilutions and assay additions are made in 10 mM potassium phosphatebuffer, pH 7.0.

[0266] X-ray crystallography of the inhibitor-aP2 complex can beperformed by one skilled in the art using contemporary biophysicalmethodologies and commercial instrumentation. Such crystallographic datacan be used to conclusively determine if a compound used in the presentinvention has embodied the structural requirement necessary forinhibition of aP2. An example of such an X-ray crystallographicdetermination is presented below:

[0267] Crystals of aP2 complexed with the inhibitors were typicallygrown by the hanging drop method. aP2, at 8.3 mg/ml, waspre-equilibrated with 1-5 mM of the inhibitor in 0.1 M Tris-HCl pH 8.0,1% w/v DMSO for four hours. 2 μl drops containing equilibrated proteinand reservoir solution at a 1:1 ratio were suspended on plastic coverslips and equilibrated against a 1 ml reservoir containing 2.6-3.0 Mammonium sulfate in 0.1 M Tris-HCl pH 8.0. Crystals typically appearedin 2-3 days and reached maximum size within 2 weeks. Data was typicallycollected on a single flash-frozen crystal (Oxford Cryosystems) using aRigaku rotating anode and an R-axis II image plate detector of a Brukermultiwire area detector. Diffraction from aP2 crystals was excellent.Diffraction was consistently observed to better than 2.0 Å resolutionoften to beyond 1.5 Å resolution. Data was processed either withDENZO/SCALEPACK (R-axis II data), or Xengen (Bruker data). XPLOR wasused for structure refinement and model building was done using themolecular modeling package CHAIN. After a single round of refinement,examination of the F_(o)-F_(c) map typically allowed facile building ofthe inhibitor into aP2 binding cavity. Iterative fitting and refinementwere continued until improvement was no longer seen in the electrondensity map or R-free.

[0268] Referring to the accompanying Figure which is a computergenerated image of a partial X-ray structure of compound XVIA bound tohuman aP2, the ball and stick figure in light gray is compound XVIA. TheArg106, Arg126, and Tyr128 residues are depicted as ball and stickfigures in dark gray. The dark spheres represent a space filling view ofthe discrete binding pocket comprised of the residues Phe16, Tyr19,Met20, Val23, Val25, Ala33, Phe57, Thr74, Ala75, Asp76, Arg78. The4-chlorophenyl substituent of compound XVIA is shown bound within thisdiscrete pocket and the hydroxyl group is bound to the Arg-Tyr-Argresidues.

1 1 1 132 PRT HOMO SAPIENS 1 Met Cys Asp Ala Phe Val Gly Thr Trp Lys LeuVal Ser Ser Glu Asn 1 5 10 15 Phe Asp Asp Tyr Met Lys Glu Val Gly ValGly Phe Ala Thr Arg Lys 20 25 30 Val Ala Gly Met Ala Lys Pro Asn Met IleIle Ser Val Asn Gly Asp 35 40 45 Val Ile Thr Ile Lys Ser Glu Ser Thr PheLys Asn Thr Glu Ile Ser 50 55 60 Phe Ile Leu Gly Gln Glu Phe Asp Glu ValThr Ala Asp Asp Arg Lys 65 70 75 80 Val Lys Ser Thr Ile Thr Leu Asp GlyGly Val Leu Val His Val Gln 85 90 95 Lys Trp Asp Gly Lys Ser Thr Thr IleLys Arg Lys Arg Glu Asp Asp 100 105 110 Lys Leu Val Val Glu Cys Val MetLys Gly Val Thr Ser Thr Arg Val 115 120 125 Tyr Glu Arg Ala 130

What is claimed is:
 1. A method for treating atherosclerosis whichcomprises administering to a mammalian species in need of treatment atherapeutically effective amount of an aP2 inhibitor.
 2. The method asdefined in claim 1 wherein the aP2 inhibitor binds to the aP2 proteinand inhibits its function and/or its ability to bind free fatty acids.3. The method as defined in claim 1 wherein the aP2 inhibitor contains ahydrogen bond donator or acceptor group and interacts directly orthrough an intervening water molecule either by ionic or hydrogenbonding interactions, with one, two, or three of the three amino acidresidues, designated as Arg 106, Arg 126 and Tyr 128 in human aP2 withinthe aP2 protein.
 4. The method as defined in claim 3 wherein thehydrogen bond donator or acceptor group is acid in nature.
 5. The methodas defined in claim 3 where said aP2 inhibitor contains an additionalsubstituent which binds to (in) and/or interacts with a discrete pocketwithin the aP2 protein defined roughly by the amino acid residues Phe16, Tyr 19, Met 20, Val 23, Val 25, Ala 33, Phe 57, Thr 74, Ala 75, Asp76, Arg 78 in human aP2.
 6. The method as defined in claim 5 whereinsaid additional substituent in said aP2 inhibitor is hydrophobic innature.
 7. The method as defined in claim 5 in which the through spacedistance from the hydrogen bond donor/acceptor group and the additionalsubstituent group in said aP2 inhibitor is within the distance of about7 to about 15 Angstroms.
 8. The method as defined in claim 1 whereinType II diabetes is treated.
 9. The method as defined in claim 1 whereinthe aP2 inhibitor is employed in the form of a pharmaceuticallyacceptable salt thereof or a prodrug ester thereof.
 10. The method asdefined in claim 1 wherein the aP2 inhibitor includes an oxazole oranalogous ring, a pyrimidine derivative or a pyridazinone derivative.11. The method as defined in claim 10 wherein the aP2 inhibitor is asubstituted benzoyl or biphenyl-2-oxazole-alkanoic acid derivative, anoxazole derivative, a 2-thio-4,5-diphenyloxazole S-derivative, aphenyl-heterocyclic oxazole derivative, a diaryloxazole derivative, a4,5-diphenyloxazole derivative, an oxazole carboxylic acid derivative, aphenyloxazolyloxazole derivative, or a 2-(4,5-diaryl)-2-oxazolylsubstituted phenoxyalkanoic acid derivative.
 12. The method as definedin claim 10 wherein the aP2 inhibitor is a 2-benzyloxypyrimidinederivative, a dihydro(alkylthio)(naphthylmethyl) oxypyrimidinederivative, a thiouracil derivative, or an α-substitutedpyrimidine-thioalkyl or alkyl ether derivative.
 13. The method asdefined in claim 10 wherein the aP2 inhibitor is a pyridazinone aceticacid derivative.
 14. The method as defined in claim 10 wherein the aP2inhibitor is (I) a substituted benzoylbenzene or biphenyl alkanoic acidderivative having the structure: A(CH₂)_(n)O—B  I wherein A is a grouphaving the formula

wherein X is —N— or

Z is

—S— or —O— R¹ is hydrogen, lower alkyl or phenyl; R² is hydrogen orlower alkyl; or R¹ and R² taken together form a benzene ring, with theproviso that when X is —N—, Z is other than

R³ is hydrogen or lower alkyl; n is 1-2; B is

wherein Y is OR⁵ or N(OH)R⁸; R⁴ and R⁵ are each, independently, hydrogenor lower alkyl; R⁶ is hydrogen, halo or nitro; R⁷ is

R⁸ is lower alkyl; m is 0-3; or a pharmacologically acceptable saltsthereof; (II) oxazole derivatives which have the structure

in which; R and R′ are identical or different and represent a hydrogenatom or an alkyl radical containing 1 or 2 carbon atoms, R₁ and R₂ areidentical or different and represent hydrogen or halogen atoms oralkyloxy radicals in which the alkyl portion contains 1 to 4 carbonatoms in a straight or branched chain, and n equals 3 to 6, as well totheir salts; (III) 2-thiol-4,5-diphenyloxazole S-derivatives which havethe structure

wherein m is 0, 1 or 2, n is 1 and R represents hydroxy, alkoxy oramino, and pharmaceutically acceptable addition salts thereof; (IV)azole derivatives of the structure

wherein R₁ is carboxyl, esterified carboxyl or other functionallymodified carboxyl group; R₂ and R₃ each are aryl of up to 10 carbonatoms; A is C_(n)H₂n in which n is an integer from 1 to 10, inclusive;and Z is O or S, and physiologically acceptable salts thereof; (V)phenyl-heterocyclic oxazole derivatives which have the structure

R is CH₂R²; R¹ is Ph or Th; R² is

R³ is H, or C₁-C₄ lower alkyl; or pharmaceutically, acceptable saltthereof; (VI) diaryloxazole derivatives having the structure

wherein R¹ is carboxy or protected carboxy, R² is aryl, R³ is aryl, A¹is lower alkylene, A² is bond or lower alkylene and -Q- is

(in which

is cyclo (lower)alkane or cycle(lower)alkene, each of which may havesuitable substituent(s)); (VII) 4,5-diphenyloxazole derivatives havingthe structure

wherein R is H or C₁-C₅ lower alkyl, X is N or CH, Y is H or CO₂R¹, orCOR², provided that when X is CH, Y is not H, R¹ is C₁-C₅ lower alkyl,or phenylmethyl, and R² is C₁-C₅ alkyl;

wherein R is H or C₁-C₅ lower alkyl, X is (CH₂)_(n) or para or metasubstituted phenyl wherein the substituent is OR², R² is C₁-C₅ alkyl,and n is an integer of 4 to 8, and pharmaceutically acceptable saltsthereof; (VIII) oxazole carboxylic acid derivatives having the structure

wherein Y and Z are independently hydrogen or together form a bond; X isCN, CO₂R¹ or CONR²R³; R and R¹ are independently or together H, Na, orC₁-C₅ lower alkyl; R² and R³ are independently- or together H, or C₁-C₅lower alkyl; or alkali metal salt thereof; (IX) phenyloxazolyloxazolederivatives having the structure

wherein X is

Y is CH₃, Ph, or OH, provided that when Y is OH, the compound exists inthe keto-enol tautaumerism form

R¹ is Ph or Th; R² is CH₂R³; R³ is CO₂R⁴; R⁴ is H or C₁-C₅ lower alkyl;R⁵ is H or CH₃; R⁶ is OHCHN or H₂N; and R⁷ is H or OH; orpharmaceutically acceptable salt thereof; (X) 2-(4,5-diaryl)-2-oxazolylsubstituted phenoxyalkanoic acids and esters having the strucutre

(wherein n is 7-9 and R is hydrogen or Lower alkyl; or when R ishydrogen, the alkali metal salt thereof),

wherein R₁ is phenyl or thienyl; R₂ is hydrogen, lower alkyl or togetherwith CO₂ is tetrazol-1-yl; X is a divalent connecting group selectedfrom the group consisting of CH₂CH₂, CH═CH, and CH₂O; Y is a divalentconnecting group attached to the 3- or 4-phenyl position selected fromthe group consisting of OCH₂, CH₂CH₂ and CH═CH, or when R₂ is hydrogen,an alkali metal salt thereof; (XI) substituted 4,5-diaryl heterocycleshaving the formula

in which each group Ar is the same or different and is optionallysubstituted phenyl or optionally substituted heteroaryl; X is nitrogenor CR¹; Y is nitrogen, N(CH₂)_(n)A or C(CH₂)_(n)A; Z is nitrogen, oxygenor N(CH₂)_(n)A, and the dotted line indicates the optional presence of adouble bond so as to form a fully unsaturated heterocyclic ring; R¹ ishydrogen, C₁₋₄alkyl, optionally substituted phenyl or optionallysubstituted heteroaryl; n is 4 to 12; and A is CO₂H or a grouphydrolysable to CO₂H, 5-tetrazolyl, SO₃H, P(O) (OR)₂, P(O) (OH)₂, orP(O) (R) (OR) in which R is hydrogen or C₁₋₄alkyl, or a pharmaceuticallyacceptable salt thereof; (XII) compounds which have he structure

Where X is O or S; R₁ is H, phenyl or phenyl substituted with F, Cl orBr or alkoxy, R₂ is H, alkyl, phenyl or phenyl substituted with F, Cl orBr or alkoxy, and R₃ is H or alkyl; (XIII) 2-benzyloxypyrimidinederivatives having the following structure

wherein R¹ and R² are each independently H, a halogen, hydroxyl, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₃-C₅ alkenyl, C₃-C₅ alkynyl, C₁-C₄ alkoxy,C₁-C₄ haloalkoxy, C₃-C₅ alkenyloxy, C₃-C₅ alkynyloxy, C₁-C₄ alkylthio,or phenyl, with the proviso that at least one of R¹ and R² must behydroxyl; n is an integer of 0 to 5; and each X which may be identicalor different if n is greater than 1, is a halogen, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₇-C₉ aralkyloxy, phenyl,hydroxymethyl, hydroxycarbonyl, C₁-C₄ alkoxycarbonyl, or nitro; (XIV)dihydro (alkylthio)-(naphthylmethyl)-oxopyrimidines which have thestructures

R¹=sec-butyl, cyclopentyl, cyclohexyl; R²=H, CH₃, including tautomers ofthe above; (XVI) α-substituted pyrimidine-thioalkyl and alkylethercompounds which have the structure

where m is 0 or 1; R¹ is selected from —CO₂R₅₃, —CONR₅₄R₅₅,

where s is 0 or 1, and R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, and R₂₅ are the same ordifferent and are selected from —H, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆alkoxy, C₁-C₆ alkylthio, C₃C₈ cycloalkyl, —CF₃, —NO₂, -halo, —OH, —CN,phenyl, phenylthio, -styryl, —CO₂(R₃₁), —CON(R₃₁) (R₃₂), —CO(R₃₁),—(CH₂)_(n)N(R₃₁) (R₃₂), —C(OH) (R₃₁ (R₃₃), —(CH₂)_(n)N (R₃₁) (CO(R₃₃))(CH₂)_(n)N(R₃₁) (SO₂ (R₃₃)) or where R₂₀ and R₂₁, or R₂₁ and R₂₂, or R₂₂and R₂₃ are taken together to form a five or six-membered saturated orunsaturated ring containing 0 or 1 oxygen, nitrogen or sulfur, where theunsaturated ring may be optionally substituted with 1, 2 or 3, C₁-C₆alkyl, C₁-C₆, alkoxy, —OH, —CH₂OH(CH₂)_(n)—N(R₃₁)(R₃₂), —C₃-C₈cycloalkyl, —CF₃, -halo, CO₂ (R₃₁), —CON(R₃₁) (R₃₂), —CO(R₃₁),—(CH₂)_(n)N(R₃₁) (CO(R₃₃), —(CH₂)_(n)N(R₃₁) (SO₂ (R₃₃)), —CN, —CH₂CF₃ or—CH(CF₃)₂, or phenyl and the saturated ring may be optionallysubstituted with 1, 2 or 3, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, —OH, —CH₂OH or—(CH₂)_(n)—N(R₃₁) (R₃₂) or one oxo (═O); where n is 0-3 and R₃₁, R₃₂ andR₃₃ are the same or different and are selected from —H, C₁-C₆ alkyl,phenyl optionally substituted with 1, 2 or 3-halo, C₁-C₆ alkyl, C₁-C₆alkoxy, —CF₃, —OH or —CN, or where R₃₁ and R₃₂ taken together with theattached nitrogen to form a ring selected from -pyrrolidinyl,-piperidinyl, -4-morpholinyl,-4-thiomorpholinyl, -4-piperazinyl,-4-(1-C₁-C₆alkyl)piperazinyl, or a member selected from 1-cyclohexenyl,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-imidazolyl, 4-imidazolyl,2-benzothiazolyl, 2-benzoxazolyl, 2-benzimidazolyl, 2-oxazolyl,4-oxazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl,5-methyl-3-isoxazolyl, 5-phenyl-3-isoxazolyl, 4-thiazolyl,3-methyl-2-pyrazinyl, 5-methyl-2-pyrazinyl, 6-methyl-2-pyrazinyl,5-chloro-2-thienyl, 3-furyl, benzofuran-2-yl, benzothien-2-yl,2H-1-benzopyran-3-yl, 2,3-dihydrobenzopyran-5-yl, 1-methylimidazol-2-yl,quinoxalin-2-yl, piperon-5-yl, 4,7-dichlorobenzoxazol-2-yl,4,6-dimethylpyrimidin-2-yl, 4-methylpyrimidin-2-yl,2,4-dimethylpyrimidin-6-yl, 2-methylpyrimidin-4-yl,4-methylpyrimidin-6-yl, 6-chloropiperon-5-yl,5-chloroimidazol[1,2-a]pyridin-2-yl, 1-H-inden-3-yl,1-H-2-methyl-inden-2-yl, 3,4-dihydronaphth-1-yl,S-4-isopropenylcyclohexen-1-yl or 4-dihydronaphth-2-yl; where R₅₃ isselected from —H, C₁-C₆alkyl, C₃-C₆cycloalkyl, phenyl (optionallysubstituted with 1,2, or 3-halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, —CF₃, —OH,—CN), or a five or six-membered unsaturated ring containing 0 or 1oxygen, nitrogen or sulfur, where the unsaturated ring may be optionallysubstituted with —H, C₁-C₆ alkyl, C₁-C₆ alkoxy, —OH, —CH₂OH, or—(CH₂)_(n)—N(R₃₁)(R₃₂); where R₅₄ and R₅₅ being the same or differentare selected from —H, C₁-C₆ alkyl, allyl, or phenyl (optionallysubstituted with 1, 2 or 3-halo, C₁-C₆ alkyl, C₁-C₆ alkoxy or —CF₃), ortaken together with the attached nitrogen to form a ring selected from-pyrrolidinyl, -piperidinyl, -4-morpholinyl, -4-thiomorpholinyl,-4-piperazinyl, -4-(1-C₁-C₆alkyl)piperazinyl; R₄₁ and R₄₂, being thesame or different, are selected from —H and C₁-C₄ alkyl; R₁₂ is selectedfrom —H, C₁-C₆ alkyl, —C₃-C₆ cycloalkyl, —CN, —C(O)NH₂,—C(O)N(C₁-C₆alkyl) (C₁-C₆alkyl), —CO₂H, —CO₂ (C₁-C₆alkyl), —CH₂OH,—CH₂NH₂ or —CF₃; R₁₃ is selected from —H, C₁-C₆ alkyl or —CF₃; Y isselected from —S—, —S(O)—, —S(O)₂, or —O—; R₄ is —OH; R₅ is selected —H,—C₂H₄OH, —C₂H₄—O-TBDMS, halo, —C₃-C₆ cycloalkyl, C₁-C₃ alkoxy, —CH₂CH₂Clor C₁-C₄ alkyl, with the proviso that R₅ is not isobutyl; or, when R₆ ishydroxyl, R₄ and R₅ are taken together to form a five or six-memeberedsaturated or unsaturated ring which together with the pyrimidine ringform the group consisting of 7H-pyrrolo[2,3-d]pyrimidine,5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidine, furo[2,3-d]pyrimidine,5,6-dihydro-furo[2,3-d]pyrimidine, thieno[2,3-d]pyrimidine,5,6-dihydro-thieno[2,3-d]pyrimidine, 1H-pyrazolo[3,4-d]pyrimidine,1H-purine, pyrimido[4,5-d]pyrimidine, pteridine,pyrido[2,3-d]pyrimidine, or quinazoline, where the unsaturated ring maybe optionally substituted with 1, 2 or 3, C₁-C₆ alkyl C₁-C₆ alkoxy, —OH,—CH₂OH, or —(CH₂)_(n)—N(R₃₁) (R₃₂), —C₃-C₈ cycloalkyl, —CF₃, -halo,—CO₂(R₃₁), —CON(R₃₁) (R₃₂), —CO(R₃₁), —(CH₂)_(n)N(R₃₁) (CO(R₃₃)),—(CH₂)_(n)N(R₃₁) (SO₂(R₃₃)), and the saturated ring may be optionallysubstituted with 1, 2 or 3, —C₁-C₆ alkyl, C₁-C₆ alkoxy, —OH, —CH₂OH, or—(CH₂)_(n)—N(R₃₁) (R₃₂) or one oxo (═O); and R₆ is selected from —H,—OH, halo, —CN, —CF₃, —CO₂(R₆₁), —C(O)R₆₁ or —C(O)N(R₆₁) (R₆₂) where R₆₁and R₆₂ are the same or different and are selected from —H, C₁-C₆ alkyl,phenyl optionally substituted with 1, 2 or 3-halo, C₁-C₆ alkyl, C₁-C₆alkoxy, —CF₃, —OH, —CN, or where R₆₁ and R₆₂ taken together with theattached nitrogen to form a ring selected from -pyrrolidinyl,-piperidinyl, -4-morpholinyl, -4-thiomorpholinyl, -4-piperazinyl, or-4-(C₁-C₆ alkyl)piperazinyl; pharmaceutically acceptable salts,hydrates, N-oxides and solvates thereof; (XVII) compounds which have thestructure

where R₁ and R₂ are H, alkyl, aryl or arylalkyl, where the alkyl caninclude as substituents halogen, CF₃, CH₃O, CH₃S, NO₂, or R₁ and R₂ withthe carbons to which they are attached can form methylenedioxy, or R₁and R₂ can form a C₃-C₇ non-aromatic ring, or a heterocycle which can bepyridine, pyrazine, pyrimidine, pyridazine, indol, or pyrazole, or anoxygen containing heterocycle which can be pyran or furan, or a sulfurcontaining heterocycle which can be thiopyran, or thiophene; theheterocycles being optionally substituted with halogen or alkyl, R₃ andR₄ are H, alkyl, halogen, CF₃, CH₃₀, CH₃S or NO₂ or R₃ and R₄ with thecarbons to which they are attached can form a methylenedioxy group, R₅is H, and Z is a heterocycle which can be pyridine, thiazole,benzothiazole, benzimidazole or quinoline, which Z group can optionallybe substituted with halogen or alkyl.
 15. The method as defined in claim1 wherein the aP2 inhibitor has the structure


16. A pharmaceutical combination comprising an aP2 inhibitor and anothertype antiatherosclerotic agent.
 17. The combination as defined in claim16 wherein the other antiatherosclerotic agent is an MTP inhibitor, anHMG CoA reductase inhibitor, a squalene synthetase inhibitor, a fibricacid derivative, other cholesterol lowering agent, a lipoxygenaseinhibitor, an ACAT inhibitor or a PPAR α/γ dual agonist.
 18. Thecombination as defined in claim 16 wherein the antiatherosclerotic agentis pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin orfluvastatin.
 19. The combination as defined in claim 16 wherein the aP2inhibitor is present in a weight ratio to the antiatherosclerotic agentwithin the range from about 0.01 to about 100:1.
 20. A method fortreating atherosclerosis which comprises administering to a mammalianspecies in need of treatment a therapeutically effective amount of apharmaceutical combination as defined it claim 16.